Clinical Investigations of Sjogren's Syndrome

干燥综合征的临床研究

• 批准号: 8929681
• 负责人: Ilias Alevizos
• 金额: $ 118.62万
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8929681
• 关键词: Acinar Cell; Address; Agonist; Area; Autoimmunity; Autonomic nervous system; Biological Markers; Biopsy; Calcium; Cell Volumes; Cell physiology; Cells; Classification; Clinical; Clinical Research; Clinical Trials; Collaborations; Collection; Confocal Microscopy; Data; Defect; Diagnosis; Disease; Ductal Epithelial Cell; Endocrinology; Epithelial Cells; Fluids and Secretions; Functional Imaging; Functional disorder; Future; Gene Expression Profile; Genetic Materials; Gland; Goals; High-Throughput Nucleotide Sequencing; Immunology; Individual; Inflammation; Laboratories; Laboratory Study; Lead; Lymphocyte; Masks; Measures; Methods; Minor salivary gland structure; Molecular; Molecular Profiling; Mutation; Natural History; Organ; Parotid Gland; Pathogenesis; Pathologic; Patients; Phenotype; Proteins; Research; Research Project Grants; Salivary; Salivary Glands; Sampling; Scientist; Severities; Sjogren' s Syndrome; Source; Specimen; Structure; Syndrome; Therapeutic; Time; Tissue Sample; cell type; clinical phenotype; design; genetic profiling; healthy volunteer; improved; interest; laser capture microdissection; medical specialties; novel; outcome forecast

Natural history and pathogenesis of Sjgren's syndrome(SS) The primary objective of this study is to enable the collection of longitudinal clinical and laboratory data and biologic specimens to identify pathogenetic mechanisms of SS by careful clinical phenotyping of SS patients and Sjgrens-like conditions over time and collection of biologic samples for concurrent and future laboratory studies related to the pathogenesis of Sjgrens syndrome. Another objective of the study is to identify biomarker candidates associated with the diagnosis, severity, prognosis, or organ involvement in SS. Associated research projects: 1. Ex-vivo salivary gland functional imaging The molecular mechanisms underlying salivary gland secretory defects in SS is unknown. While the destruction of glandular structure can contribute to the decrease in total salivary fluid secretion, it does not explain the loss of secretion in patients who have low, or negligible, levels of inflammation in the glands (this group constitutes over 80% of the SS patients). By obtaining fresh minor salivary gland biopsies from SS patients and healthy volunteers, we examine single acinar cell function from intact acinar clusters, with confocal microscopy. We are able to measure calcium influx and release in individual cells and also measure individual cell volume changes after agonist stimulation. This has allowed us to focus on specific candidate proteins that might be responsible for the salivary gland dysfunction associated with SS 2.Trancriptome profiling of salivary glands There is an unmet need to characterize the molecular profile of the broad range of phenotypes in SS. With the advent of high throughput sequencing methods, a complete characterization of whole transcriptome of salivary glands and specifically of each of their resident cells types will greatly facilitate the sub-classification and better characterization of the genetic changes in SS patients. In SS the presence of different levels of inflammation in glands of patients present a challenge when whole glands are used as source of material. Under these circumstances, the analysis of genetic material and proteins from heterogeneous tissue sample as a whole, might mask the important changes that occur in the individual types of cells. Laser capture microdissection allows the procurement of specific cell types by dissecting out only cells of interest. We are planning to use parotid and minor salivary glands of SS patients and through laser capture microdissection isolate and characterize the genetic profile of ductal and acinar cells as well as the resident lymphocytes . Through this project proteins will also be isolated from each cell type and stored for future

干燥综合征（SS）的自然史和发病机制 本研究的主要目的是收集纵向临床和实验室数据以及生物样本，通过对SS患者和Sjobs样疾病进行仔细的临床表型分型，并收集生物样本用于Sjobs综合征发病机制相关的同步和未来实验室研究，以确定SS的发病机制。该研究的另一个目的是确定与SS的诊断、严重程度、预后或器官受累相关的生物标志物候选者。 相关研究项目： 1.离体涎腺功能成像 SS中唾液腺分泌缺陷的分子机制尚不清楚。虽然腺体结构的破坏可能导致总唾液分泌减少，但它不能解释腺体炎症水平低或可忽略的患者（该组占SS患者的80%以上）的分泌丧失。 通过从SS患者和健康志愿者获得新鲜的小涎腺活检组织，我们用共聚焦显微镜检查完整腺泡簇中单个腺泡细胞的功能。 我们能够测量单个细胞中的钙流入和释放，也可以测量激动剂刺激后单个细胞体积的变化。这使我们能够专注于特定的候选蛋白质，可能是负责与SS相关的唾液腺功能障碍 2.唾液腺转录组分析 存在未满足的需要来表征SS中广泛表型的分子谱。随着高通量测序方法的出现，唾液腺的整个转录组的完整表征，特别是它们的每种驻留细胞类型的完整表征，将极大地促进SS患者的遗传变化的亚分类和更好的表征。 在SS中，当使用整个腺体作为材料来源时，患者腺体中存在不同程度的炎症是一个挑战。在这种情况下，从异质组织样本中分析遗传物质和蛋白质作为一个整体，可能会掩盖在个别类型的细胞中发生的重要变化。 激光捕获显微切割允许通过仅解剖出感兴趣的细胞来获得特定的细胞类型。 我们计划使用SS患者的腮腺和小唾液腺，通过激光捕获显微切割，分离和表征导管和腺泡细胞以及驻留淋巴细胞的遗传特征。通过这个项目，蛋白质也将从每种细胞类型中分离出来，并储存起来以备将来使用。